Todralazine protects zebrafish from lethal effects of ionizing radiation: Role of hematopoietic cell expansion

Manali Dimri, Jayadev Joshi, Rina Chakrabarti, Neeta Sehgal, Angara Sureshbabu, Indracanti Prem Kumar

Research output: Contribution to journalArticle

Abstract

The Johns Hopkins Clinical Compound Library (JHCCL), a collection of Food and Drug Administration (FDA)-approved small molecules (1400), was screened in silico for identification of novel β2AR blockers and tested for hematopoietic stem cell (HSC) expansion and radioprotection in zebrafish embryos. Docking studies, followed by the capacity to hasten erythropoiesis, identified todralazine (Binding energy, -8.4 kcal/mol) as a potential HSC-modulating agent. Todralazine (5 μM) significantly increased erythropoiesis in caudal hematopoietic tissue (CHT) in wild-type and anemic zebrafish embryos (2.33- and 1.44-folds, respectively) when compared with untreated and anemic control groups. Todralazine (5 μM) treatment also led to an increased number of erythroid progenitors, as revealed from the increased expression of erythroid progenitor-specific genes in the CHT region. Consistent with these effects, zebrafish embryos, Tg(cmyb:gfp), treated with 5 μM todralazine from 24 to 36 hours post fertilization (hpf) showed increased (approximately two-folds) number of HSCs at the aorta-gonad-mesonephros region (AGM). Similarly, expression of HSC marker genes, runx1 (3.3-folds), and cMyb (1.41-folds) also increased in case of todralazine-treated embryos, further supporting its HSC expansion potential. Metoprolol, a known beta blocker, also induced HSC expansion (1.36- and 1.48-fold increase in runx1 and cMyb, respectively). Todralazine (5 μM) when added 30 min before 20 Gy gamma radiation, protected zebrafish from radiation-induced organ toxicity, apoptosis, and improved survival (80% survival advantage over 6 days). The 2-deoxyribose degradation test further suggested hydroxyl (OH) radical scavenging potential of todralazine, and the same is recapitulated in vivo. These results suggest that todralazine is a potential HSC expanding agent, which might be acting along with important functions, such as antioxidant and free radical scavenging, in manifesting radioprotection.

Original languageEnglish (US)
Pages (from-to)33-47
Number of pages15
JournalZebrafish
Volume12
Issue number1
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

Fingerprint

Todralazine
Zebrafish
Ionizing Radiation
ionizing radiation
Danio rerio
lethal genes
Hematopoietic Stem Cells
erythropoiesis
Embryonic Structures
cells
Erythropoiesis
beta-adrenergic antagonists
Mesonephros
aorta
Deoxyribose
Radiation Dosage
Metoprolol
gamma radiation
hematopoietic stem cells
gonads

ASJC Scopus subject areas

  • Animal Science and Zoology
  • Developmental Biology

Cite this

Todralazine protects zebrafish from lethal effects of ionizing radiation : Role of hematopoietic cell expansion. / Dimri, Manali; Joshi, Jayadev; Chakrabarti, Rina; Sehgal, Neeta; Sureshbabu, Angara; Prem Kumar, Indracanti.

In: Zebrafish, Vol. 12, No. 1, 01.02.2015, p. 33-47.

Research output: Contribution to journalArticle

Dimri, Manali ; Joshi, Jayadev ; Chakrabarti, Rina ; Sehgal, Neeta ; Sureshbabu, Angara ; Prem Kumar, Indracanti. / Todralazine protects zebrafish from lethal effects of ionizing radiation : Role of hematopoietic cell expansion. In: Zebrafish. 2015 ; Vol. 12, No. 1. pp. 33-47.
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